From Our Neurons to Yours

Is Alzheimer's an energy crisis in the brain? Inflammation, metabolism and a new path in the search for cures | Kati Andreasson

• Nicholas Weiler, Katrin Andreasson • Season 8 • Episode 10

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For decades, Alzheimer's research has focused on clearing amyloid plaques from the brain. But new drugs that successfully remove plaques have proven clinically "underwhelming", leaving the field searching for alternative approaches.

Stanford neurologist Katrin Andreasson has spent twenty years pursuing a different path—investigating how aging triggers an energy crisis in the brain's immune and support cells. Her work reveals that inflammation and metabolic dysfunction in microglia and astrocytes may be the real drivers of Alzheimer's pathology. 

Most remarkably, her recent research—supported by the Knight Initiative for Brain Resilience here at the Wu Tsai Neurosciences Institute—shows that targeting inflammation in the peripheral immune system—outside the brain entirely—can restore memory in mouse models of the disease. 

While human trials are still needed, Andreasson's findings offer fresh hope and demonstrate the critical importance of supporting curiosity-driven science, even when it challenges prevailing dogma.

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Nicholas Weiler (00:07):

This is From Our Neurons to Yours, the podcast from the Wu Tsai Neurosciences Institute at Stanford University, bringing you to the frontiers of brain science.

(00:22):

Today on the show, inflammation and Alzheimer's disease. For decades, the big hope for treating Alzheimer's disease has centered on finding a way to clear the brain of the sticky amyloid plaques that define the disorder, and in just the past few years, multiple new drugs have come out, which are, by all accounts, quite effective at doing just that. But unfortunately, what should have been a celebration has become a bit of a disappointment. A few episodes ago, we had Stanford neurologist, Mike Greicius, on the show, and he pointed out that while the new drugs do reduce plaque buildup, the clinical benefits reported are minimal, essentially undetectable to patients and their physicians. This has led to a fierce debate among the experts. Some argue for abandoning the focus on amyloid altogether. Others maintain that genetics prove amyloid is an important player in the disease, maybe we are just intervening too late. In any case, the Alzheimer's field, that had long been unified around the amyloid hypothesis, is now divided and desperate for alternative approaches.

(01:28):

Today's guest is Katrin Andreasson, a physician scientist at Stanford whose lab has spent the past two decades patiently following scientific clues to understand the links between aging, Alzheimer's and inflammation in the brain. Initially, Andreasson struggled to get funding for her research, as most people were fixated on amyloid. But she and her team have meticulously pursued a series of biological questions that have succeeded in painting a new vision of how Alzheimer's arises, as an age-related energy crisis affecting the brain's immune cells, the microglia, and other key support cells, called astrocytes. They've shown that reversing this metabolic crisis in mice bred to develop Alzheimer's disease can restore both memory and cognition. Most recently, they've made the stunning discovery that targeting age-related inflammation in the peripheral immune system, so not the brain at all, can also treat Alzheimer's symptoms in mice. That's pretty far out.

(02:33):

Now, we should also be clear, Alzheimer's has been cured in mice many times, so we need to wait for human trials before getting our hopes too high. But at a time when Alzheimer's research is facing a long sojourn in the wilderness, I was particularly excited to talk with Katrin, because her work is such a good example of the importance of curiosity-driven science, even when it goes against the brain. And plug for the Knight Initiative for Brain Resilience here at Wu Tsai Neuro, which funds some of this work, that's what this initiative is all about, cultivating new ideas about how we can keep our brains healthy and prevent neurodegenerative disease. So I asked Katrin to join us on the show, to share her scientific journey, and help us understand this promising new battle line in the fight against Alzheimer's disease.

(03:24):

Katrin Andreasson, welcome to From Our Neurons to Yours. It's so great to have you on the show.

Katrin Andreasson (03:29):

Thank you. It's a pleasure.

Nicholas Weiler (03:31):

We've had a few conversations on the topic of how the thinking in the field of Alzheimer's research has been changing over the past few years. There has been this incredible focus for many years in Alzheimer's research on amyloid plaques, these gunky accumulations of protein that we see in the brains of people with Alzheimer's, and a lot of resources and a lot of time have gone into figuring out how to clear those out of the brain. We now have drugs that seem to do that pretty well. But in the words of your colleague, Mike Greicius, who was on the show a few months ago, those drugs in the end for patients seem to be kind of underwhelming. Do you agree with that assessment?

Katrin Andreasson (04:11):

Yes. I think from a clinician standpoint, they are underwhelming. They are very expensive. So yes, I agree, we really need something much better and much more efficacious.

Nicholas Weiler (04:24):

Well, you got an award earlier this year from the Alzheimer's Association for the most impactful paper in the field of Alzheimer's research for the past two years, so congratulations on that.

Katrin Andreasson (04:35):

Thank you.

Nicholas Weiler (04:38):

And it reflects this different approach that you and your research group have been taking over the past couple of decades to thinking about the role that inflammation, and more recently, metabolism in the brain might be playing in where Alzheimer's comes from. I want to talk about this research journey, this started 20 years ago. But before we dive into that, can you tell us a little bit broadly about what is inflammation and why does it happen in the brain? Why is it so bad for the brain?

Katrin Andreasson (05:10):

Yeah. Inflammation is complex. So we absolutely need our immune cells, which give us inflammation, to defend us from viruses and bacteria, and we also need our immune cells to take care of all the cellular waste that we make in our bodies every day. So if you think about it, we make hundreds of billions of red blood cells, and they have a finite life. And immune cells, specifically macrophages, gobble these up on a daily basis. It's a huge amount of work. And so, that's just one example of an internal function of the immune system is just to keep everything humming along.

(05:51):

We have immune cells in all our organs. My lab is really focused mainly on the macrophage population, this is the first responder. It's like the firefighter who goes out there to put out the fire. If there's an infection, the macrophage is there, tries to clear it. And macrophages operate everywhere, in your liver, in your gut and in your brain. And they have a special name in the brain, they're called microglia, and they are tremendously important. And in the last couple of years now, we've really begun to appreciate the importance of the macrophage in our health, and how as they decline, so do we.

Nicholas Weiler (06:37):

Right. With aging, those macrophages get exhausted.

Katrin Andreasson (06:41):

Yeah, yeah.

Nicholas Weiler (06:42):

I just want to go back for a second, so this is something I'd love for you to help me clear up. You said that the macrophages are one of our first responder immune cells throughout the body, and in the brain, they have a special name, the microglia. Why do they have a special name in the brain? Are they the same cells, or is it a different cell with the same job?

Katrin Andreasson (06:59):

It has the same job. So it basically keeps the brain clear and pristine, it gets rid of stuff like amyloid, it also gets rid of dead synapses. They're called microglia, I think, because they're smaller than a macrophage that you find in your liver, they also look a little different. But this is the beautiful thing about macrophages is that they adapt, just like we would if we're in a different environment, if we're sitting in the liver, they have a certain function and they have a certain size and shape. If you're in the brain, which is a completely different kind of organ, where you have axons, you've got neurons, you've got neuron processes, they adjust and they have a very different shape and they also function in a different way. They're just continually sensing, they're putting feelers out, just making sure that the local microenvironment is kept pristine so that, of course, our neurons can work.

Nicholas Weiler (07:59):

Right. They do so many things, it's a mix between maintenance and custodial work, as you said, police and firefighters. If there's an infection, they're going to be involved, so just absolutely critical to keeping our brains clear and healthy and clean. So I think that many people have probably heard about the problems with brain inflammation. This is something that comes up, for example, talking about long COVID, that there seems to be elevated inflammation in the brain, it comes up with aging, inflammation is clearly a big problem. What is inflammation actually, what does that mean?

Katrin Andreasson (08:36):

So yeah, when we think about inflammation, we think about the detrimental component of inflammation. And so, this is something where you get a lot more production of inflammatory factors that have bad effects on the target cells. For example, if you think about aging, one of the most common age inflammatory diseases is frailty, muscle wasting, loss of strength, and that is the effect of inflammation on the muscle, so you lose muscle mass. Another example is a very common syndrome, atherosclerosis. So many people have heart disease and vascular disease, that's also inflammation, because you have, within the walls of the blood vessels, the arteries in particular, you get deposition of cholesterol, and then in come the macrophages, they're trying to clear it, they're trying to do their job. But there's so much of it, of this cholesterol, that the macrophages actually get sick and they become inflamed, and so then they recruit other cells, and so that's bad inflammation. There's so many examples, metabolic syndrome, where we eat too much and we eat the wrong things.

Nicholas Weiler (09:53):

And that's obesity and diabetes and so on?

Katrin Andreasson (09:55):

Yeah, exactly. And the tissue, it's called the adipose tissue, so this is the tissue in the belly that gets bigger and bigger, it's full of macrophages. And these macrophages are just putting out, churning out all these nasty cytokines and chemokines, so these are immune factors that signal to the rest of the body. And one of the side effects, unfortunately, is development of insulin resistance, and that predisposes people to diabetes. So there are many examples of age-associated inflammatory diseases. Chronic arthritis, you have chronic inflammation in your joints. Periodontitis, big one, of the gums, a huge risk factor for Alzheimer's.

Nicholas Weiler (10:40):

Oh, interesting.

Katrin Andreasson (10:42):

There's just so many inflammatory diseases that get worse with aging, unless we can fix it, which diet and exercise really are the current best therapies, and they can work actually quite well, but we don't have that magic pill yet.

Nicholas Weiler (10:58):

Right. Well, one of the things that's so interesting here is we talked a little bit a moment ago about the idea that, well, Alzheimer's disease involves this buildup of these amyloid plaques in the brain, so if we could clear those out, maybe we'd clear up the disease. So far, it doesn't seem like it works that way. And one of the observations that many people have made, and that you've been following, is, well, why does Alzheimer's happen as we get older? And maybe the amyloid, maybe it plays a triggering role, maybe it's something that is actually more of a side effect, that amyloid is also caused by these processes that go on during aging. But we somehow need to get to the root causes so that we can figure out when do we need to intervene, and what is the best target?

(11:53):

So in pursuing inflammation, you've told me that the inspiration for your work came in the early 2000s, when researchers in the US and Canada discovered that people who regularly took these non-steroidal anti-inflammatory drugs, which is the fancy name for drugs like ibuprofen or Advil, for several years, had a significantly reduced risk of Alzheimer's disease. Can you take us back in time? I remember that being a big deal. But I want to know, what was your reaction to seeing that research come out?

Katrin Andreasson (12:26):

Yeah, that's kind of what got us started. So these studies were done across the globe. Actually, one of the studies was done in the Netherlands, where they have nationalized medicine, so they could track everybody. Another one, which was a very compelling one, was done out of the VA. But basically, what they looked at, and this is super important, these were cognitively normal people, so they had absolutely not a whiff of anything, and they would take NSAIDs for aches and pains. It didn't even have to be every day, it was just the use of taking these NSAIDs.

Nicholas Weiler (13:06):

And NSAID, that's the abbreviation for these non-steroidal anti-

Katrin Andreasson (13:08):

Oh yeah, sorry, non-steroidal-

Nicholas Weiler (13:11):

We don't want to keep saying non-steroidal anti-inflammatory drugs.

Katrin Andreasson (13:13):

Yeah, it's too long.

Nicholas Weiler (13:14):

Let's just say NSAIDs.

Katrin Andreasson (13:15):

Yeah. But things like ibuprofen, indomethacin, not Tylenol and not aspirin, so those are not quite the same. But people who would take those, it would take a while, and this was best illustrated in the study out of the VA in 2008, it took about four to five years to actually see this effect, where people had this sudden drop in their risk of getting Alzheimer's disease. It was as big as 25%, which is considerable. So that got me thinking, well, maybe inflammation is something here. And of course, at the time, nobody wanted to hear anything except amyloid, amyloid, amyloid. I have all these sad stories of trying to get grants from the NIH and getting continually rejected and nearly quitting and going into the clinic.

(14:09):

But eventually, things did work out, and we started to look at this pathway. And NSAIDs, they block a very particular set of enzymes, they're called the cyclooxygenases, and there's two forms. And one of them, we call it affectionately COX2, cyclooxygenase-2 is very... It's like the mother of all inflammatory enzymes, because it makes something called a prostaglandin. And there are several prostaglandins, they do very different things in the body, but one of the prostaglandins is the immune inflammatory modulator, and that's called prostaglandin E2. And so, that's what we've spent the last 20-some years looking at this pathway and how that would be involved in driving Alzheimer's risk.

Nicholas Weiler (15:05):

So before we dive too deep into that, you've done this amazing work breaking down this pathway, but I want to just dwell on the NSAIDs for just a moment more. You mentioned that the NSAIDs are distinct from aspirin and from Tylenol. What exactly are NSAIDs, what are they doing?

Katrin Andreasson (15:24):

Yeah. So NSAIDs are blocking both cyclooxygenases, so there's COX1 and COX2. Tylenol, it's still not clear how it works, or at least I haven't been keeping up with it, but it's not really a COX1/COX2 blocker, and aspirin is just very specifically a COX1 blocker. And the specificity of what these drugs do really has to do with in what cells you are making the COX1 or COX2. And so, for a long time, aspirin, and it is very well-known that it causes platelets to thrombose, and so that's the benefit, the cardioprotective effects of aspirin. Although, this is all now slightly put into question more recently with some new studies.

Nicholas Weiler (16:12):

It's funny, these are such tried and true drugs, but we're still learning new things about them.

Katrin Andreasson (16:17):

Yeah.

Nicholas Weiler (16:18):

Are they all acting on inflammation, or is that something that is particularly true of ibuprofen?

Katrin Andreasson (16:23):

Well, ibuprofen has the benefit that it hits both COX1 and COX2. So COX2 really is the inflammatory enzyme, but COX1 is also helping out, so it's nice to hit both of them. And so, that's why these NSAIDs are very good for aches and pains, and of course, this preventive effect. I have to say that these early studies, people got very excited about them, and then they started trying NSAIDs in people with cognitive decline, and they did not work.

Nicholas Weiler (16:55):

Interesting.

Katrin Andreasson (16:56):

And that's why the whole field is sort of confused, because sometimes people don't distinguish between the preventive in normal cognition and potentially therapeutic, and it did not work at all, and once cognitive decline had set in, the ship had sailed.

Nicholas Weiler (17:13):

Right. I think that it's hard for us to understand, and maybe this just hasn't percolated from the lab into the broader culture. By the time cognitive problems are happening in Alzheimer's disease and many other disorders like this, stuff has been going wrong in the brain for many years already.

Katrin Andreasson (17:31):

Oh, so long.

Nicholas Weiler (17:32):

And the brain has so many ways to adapt, the brain is really good at making do with what it's got. So these things might be killing off brain cells and synapses for decades, and the brain is adapting and adapting and finding new ways of getting stuff done. By the time other people start to notice, or you start to notice yourself, that may be too late. And so, one of the things that's so challenging is, how do we catch it early? What are we trying to catch, for one thing, and how do we get there early enough that if we can fix it, it means that we're preventing something that hasn't happened yet? I guess medicine isn't always very good at that. So why was it not the recommendation to just everyone should be taking NSAIDs?

Katrin Andreasson (18:12):

Ah, well, that's a very critical question. It is not a good idea and people should not go and start taking NSAIDs, because they have side effects and they block the top of the pathway, which is the generation of the precursor of five prostaglandins. There's not just one, but there are five.

Nicholas Weiler (18:34):

And these are these inflammatory signaling molecules, the prostaglandins?

Katrin Andreasson (18:37):

Yeah, yeah, right. So five prostaglandins, but only one is really involved in inflammation, the other ones are super important. For example, we have something called prostacyclin, which would be blocked by an NSAID, and prostacyclin is super important in allowing your blood vessels to dilate. If you don't have that, your blood vessels are constricting and you get high blood pressure. We have another prostaglandin, it's called PGD2. You don't want to block that either, because that's very important in sleep-wake cycle. So these other prostaglandins, there's the other four, have very important functions. So by going at the very top of the pathway with the NSAIDs, you're actually blocking not just PGE2, which turns out to be probably the bad guy, but you're also blocking the other four, which are very important. So it's not a good idea to take NSAIDs.

(19:36):

What you want to do is you want to just move down the pathway inch by inch until you hit the sweet spot, which is what I think we have now finally done, after all this time, figured out. We know it's now PGE2 that's really the important prostaglandin. And then, after that, we had to figure out what receptor, it's like a key and a lock, a receptor binds the prostaglandin, but there are four receptors for PGE2, so we had to spend many years parsing that out until we finally got the answer. So yeah, it's a long haul.

Nicholas Weiler (20:16):

Yeah. These original observations were in, was it 2001, 2003, I think?

Katrin Andreasson (20:23):

Yeah, something like that, yeah. That's when I started my lab, yeah.

Nicholas Weiler (20:26):

So as you said, you've been working out this pathway. Okay, we know NSAIDs are reducing Alzheimer's risk, but we don't want to be giving people NSAIDs, so what are they doing? You mentioned that they're targeting this particular COX receptor, I think you called it the mother of all inflammatory molecules, which is great. And then, okay, what does that do? So the COX receptor is making these prostaglandins get released, that are these signaling molecules. Which one of those is the bad guy? You identified PGE2. It looks like that one is elevated... There was evidence that that one was actually elevated in people with Alzheimer's, is that right?

Katrin Andreasson (21:00):

Yes, and this was actually Tom Montine, when he was at University of Washington, he's at Stanford now though. His lab looked at cerebral spinal fluid from healthy patients and patients with Alzheimer's, and lo and behold, the PGE2 levels in that cerebral spinal fluid were sky-high. We were very happy to see that as well. So then, it was just a matter of now really drilling down on that pathway and figuring out which of the PGE2 receptors is the bad guy, and we figured that out. And then, how does it work? What does it regulate? Because obviously, receptors, they signal to the cell and the cell transcribes new genes and makes new proteins in response to the PGE2 signaling. Yeah, we've been the tortoise and the hare. I'm definitely the tortoise.

Nicholas Weiler (22:00):

Well, just in time, because now, amyloid... Not to trash amyloid too much, it is the thing that defines Alzheimer's disease, it was important to try. But we need new approaches, we need to be thinking about what are the early causes. And man, Katrin, biology is complicated.

Katrin Andreasson (22:18):

Yes, it is. It's fun.

Nicholas Weiler (22:19):

It is fun. It is fun. All of these different receptors, all these signaling molecules, they all do different things in the cell. I think for someone who's not in the field particularly just saying, "How do you break down this puzzle and figure out, okay, which of these things do we target?" And I think what you just said is so important, what is it doing to the cell? Why are these cells getting unhealthy? And to do that, you need to go through all these signaling pathways, understand what's going wrong and so on.

(22:45):

But I think one of the things that I found so fascinating in grappling with some of the science, which I have to say, it took me quite a while to go through all this stuff, and I probably still don't understand it, is this question that's not just about what are these molecules with funny names, it's what is actually happening to these cells that play such an important role in our neurological health and in our health overall as we age? So let's get to that a little bit. So we've mentioned a bunch of these molecules, and listeners, you probably do not need to remember the names of all of these molecules. But the point is there's a signaling pathway that's involved in inflammation, and your team was able to track down what are the signals, what are the receptors, and you could delete that particular molecular receptor in these cells, and in mouse models of Alzheimer's disease, they got better, they improved their memory and cognition. These were older mice with a lot of amyloid, and it really improved their cognition, right?

Katrin Andreasson (23:43):

Yeah. We haven't actually published that yet, but-

Nicholas Weiler (23:45):

Oh, I'm sorry. Excuse me.

Katrin Andreasson (23:47):

No, no, it's fine, it's fine, yeah. We did look at Alzheimer mice, but we were not initially looking at cognition, because I think at the time we were still pretty green. But we were looking at amyloid, actually, and it looks like if you delete the EP2 receptor, which is the bad receptor that binds PGE2, these microglia in the brain suddenly become super healthy and they can gobble up the amyloid and they can clear it, and in the process, the brain and the neurons become much, much healthier. So that was the first part.

(24:24):

And then, more recently, we figured out that in aging, if you do the same thing, if you delete EP2 just in macrophages, you get these tremendous effects on cognition, you can prevent age-associated cognitive decline. And I want to do a shout-out for a brilliant MD-PhD student who basically did a lot of these studies, and also was instrumental in getting us down on this track of real mechanism, like how does it really work? And it works actually through energy metabolism, of all things, he figured this out. And it's just been such a ride to try to figure this out, it's like being a detective and trying to find the truth.

Nicholas Weiler (25:12):

Right. And to track down, okay, what are we going to do about it? So I'd love to hear what's your model of why these cells are getting sick, particularly with age? Because I think that the connection here, this doesn't do a lot if there isn't amyloid and it doesn't do a lot in young mice, but somehow, with the combination of aging and amyloid, I think, correct me if I'm wrong here, something is going wrong with this EP2 pathway that is causing these macrophages and microglia to get sick. So at a high level, what do you think is happening to these cells?

Katrin Andreasson (25:48):

Well, you mentioned amyloid and you mentioned aging, and the one thing they have in common is detrimental inflammation, and that's caused in part by these cells, these macrophages and microglia, getting sick. Why do they get sick? Well, we can say that with aging, we suffer a decline in our energy metabolism. It's like an old battery that barely works anymore. And so, if you're an immune cell, if you're a macrophage, and you're supposed to be cleaning things up and defending against viruses and bacteria and things like that, if you don't have enough energy, you're not going to be able to do your job very well, you're going to have this anemic response.

(26:32):

And so, what we found, that as macrophages age and as microglia age, they lose key energy processes, and that translates into a steady deterioration in their immune functions. So whereas they should be keeping us healthy, they actually can't clear bacteria, viruses, debris, so amyloid builds up. So it's just this feed-forward cycle that just gets worse and worse. And so, that's what happens in aging. And to a certain extent, if you think about amyloid, when it starts to accumulate, is a really irritating substance. It activates-

Nicholas Weiler (27:16):

It's basically a cellular byproduct, right? There's an amyloid precursor protein, it gets cleaved, and if it's not cleaned up properly, it starts sticking together and making these plaques.

Katrin Andreasson (27:26):

Yeah. And the cells around the amyloid just really don't like it.

Nicholas Weiler (27:30):

Right. It's like plaque on your teeth almost.

Katrin Andreasson (27:31):

Yeah. It's like periodontitis, constant infection. I keep coming back to periodontitis, but it's such a simple example of chronic inflammation that is linked to all sorts of bad stuff.

Nicholas Weiler (27:45):

And our microglia are no longer brushing our brains appropriately.

Katrin Andreasson (27:49):

Yes, exactly, right, so that's kind of how we think about it. And the other thing I wanted to highlight, the human genetics that has been done over the last 10, 15 years, where you can look at people's genetics, look at their genomes, has clearly come up with this fact that variants of immune genes are actually the most associated with Alzheimer's. So that was a huge advance, I think, in the field, and this was relatively recently. So that's another reason why we have to think about inflammation, not just for Alzheimer's, but other similar inflammation-related diseases.

Nicholas Weiler (28:33):

There are a couple of things in this... I don't want to get too sidetracked, because I think that we've got the major idea here, that with age, our immune system is getting tired, exhausted, is not able to do its normal cleanup duties, which allows more amyloid to build up. The amyloid causes more inflammation in these cranky, tired-out immune cells, that makes the immune cells more inflammatory and less able to clear up the amyloid, and so it just gets worse and worse.

(29:01):

But there are a couple of little things in there that I thought were cool, which is, tell me if I understood this correctly, you're thinking that this prostaglandin signaling is normally there to switch cells into a energy-conserving, low-power mode that actually helps in an acute crisis like stroke where there's oxygen deprivation. Did I read that right?

Katrin Andreasson (29:22):

Yeah.

Nicholas Weiler (29:23):

So there's this low-power mode that cells can go into that can help them survive in an emergency, but that with aging and this general exhaustion of the system, they get stuck in this low-power mode all the time, which starves the cells, and that's one of the things that ages these immune cells and makes them so cranky and inflammatory.

Katrin Andreasson (29:45):

Yeah, yeah. That's a really good way to put, low-power mode, I'm going to use that. That's a very good way to explain this, thank you.

Nicholas Weiler (29:52):

Okay. So these cells get stuck in their low-power mode, they're no longer cleaning up, they're getting more inflammatory. Amyloid is maybe a trigger for that. And then, it just snowballs into this vicious cycle. So I think you mentioned that it was hard to get people's attention to some of this stuff early on because people were so focused on amyloid, and you even said it, there are a lot of grant applications you sent in on this that did not get funded. That must have been-

Katrin Andreasson (30:25):

Yeah, so discouraging, yes.

Nicholas Weiler (30:28):

... difficult. And you said you were thinking of just going back to medicine and getting out of research entirely.

Katrin Andreasson (30:32):

Yeah, yeah. I was starting to look at the local hospital, they needed a neurologist. But thankfully, I think there was a very, very kind soul at the NIH who took pity on me, because this was my very first grant, and somehow gave me 50,000, which allowed me to limp along. And then, things changed for the better. There was a program called the Beeson Award, and that really actually made all the difference, given by the American Federation for Aging Research. So I think if it hadn't been for that, I would probably be a doctor somewhere.

Nicholas Weiler (31:13):

Well, it really does seem like things have changed. I want to get to the really interesting newer work on where the microglia work is headed as far as developing therapeutics.

Katrin Andreasson (31:25):

Actually, so this is the other interesting discovery we've been making, is that, for example, with the EP2 pathway, we don't actually have to target the microglia, we can inhibit the EP2 signaling in just macrophages in the periphery.

Nicholas Weiler (31:42):

And that's so surprising, because there's been this model forever that there's this blood-brain barrier, and the immune system from the periphery is too rowdy and rambunctious to be allowed into the brain, so they're separate. But if you can target this system in the periphery and have effects on the brain, what does that mean about our whole model of how the brain's immune system works?

Katrin Andreasson (32:04):

Well, yeah, that's the thing, we're a bit of the odd man out here. But I really believe that we could probably target the periphery and not even have to get in the brain. Just based on a lot of data that's now coming out, there's this concept that the periphery does influence brain function. The question is, could you exclusively target the peripheral immune system to get benefits and brain resilience and things like that? I think it's possible, at least in experimental models, whether that will translate into humans, we just don't know.

Nicholas Weiler (32:41):

Yeah. And you've got funding now from the Knight Initiative here at Wu Tsai Neuro to do some of that work.

Katrin Andreasson (32:48):

Yes, yes, thank you, yes. We really think that the peripheral immune system, especially macrophages, are huge drivers of brain health.

Nicholas Weiler (32:55):

That's really exciting. Is this getting translated into clinical trials yet, or is this still pretty early-stage, trying to target these prostaglandin inflammatory pathways?

Katrin Andreasson (33:04):

Yeah, that's tough, that is tough. I think the thing that we've been working on that's actually much closer to translation is in the astrocytes, which is, again, an immune pathway, and it's actually an immune pathway that can be regulated by PGE2, so that kind of puts everything together. And that is the enzyme in the astrocytes called IDO1 that makes a metabolite called kynurenine, and that is actually, if you think about translation, probably much, much closer, because, fortunately, there have been a lot of IDO1 inhibitors developed in the cancer field. And so, that to me is probably much closer than anything targeting the other to EP2 at this point.

Nicholas Weiler (33:55):

We've been talking mostly about microglia, the brain's immune cells, and maybe their equivalents outside the brain, the macrophages. But in 2024, you had this amazing study, and this is what you won this award for earlier this year, looking at a parallel process going on in Alzheimer's disease that affects astrocytes, which are another type of brain cell that's really important for supporting neurons. I was trying to think of a good metaphor for this. One of the things they do is they keep neurons fueled up, like a pit crew for a fancy race car. Neurons take a lot of energy, and so the astrocytes, one of their jobs is to provide extra energy for the neurons. So can you tell us first, what got you thinking about astrocytes and their metabolism? And then, I'll ask you about the results.

Katrin Andreasson (34:41):

Yeah. So this pathway, where you take the tryptophan, which is an essential amino acid, you have to eat it, and it gets converted to this molecule called kynurenine, and this is actually a very important immune pathway. So it's in macrophages, it's in T cells, B cells, and we had actually been examining that pathway in macrophages. There's a long backstory here, where we had anticipated one outcome and we found the exact opposite, which pointed us to a completely new cell, which was not the microglia or the macrophage, but the astrocyte, which happens to also have a lot of this particular enzyme. And there's not a whole lot known about what this does in the brain, there had been some links with schizophrenia because of a downstream metabolite of kynurenine, so we just shifted.

(35:43):

This is the important thing with science, you have to be flexible, you have to be open. So we started looking at astrocytes, and again, this is Paras Minhas, our brilliant MD-PhD student who spearheaded this work, turned out that in astrocytes, there was actually also a metabolic component, just like we had been studying in macrophages and microglia, we had really zoomed in on the metabolism and how that influenced function. So in the astrocyte, it was actually very similar, except in this case, by changing the astrocyte metabolism, since astrocytes have a very key role in supporting neurons metabolically, so astrocytes will give neurons something called lactate, which is an energy molecule, so by changing the astrocyte metabolism so that they could give neurons more lactate, we discovered this very new function of this immune pathway in the brain. And basically, the punchline is that we looked mainly at amyloid and tau models, so these would be models of Alzheimer's disease pathology.

Nicholas Weiler (36:57):

In mice?

Katrin Andreasson (36:58):

In mice, yeah, in mice. In those models, what happens is the astrocytes just get exhausted, similar to what we saw in aging macrophages. They just get tired and they don't make enough lactate basically to give to the neuron. But if we inhibit this particular pathway, this IDO1 enzyme, and we reduce its product, called kynurenine, by a very complex signaling mechanism, which is all described in detail in the paper, we can actually get them to make more lactate and thus rescue neuronal metabolism.

(37:36):

And I think the exciting thing is that this could be a third rail, so to speak. Alzheimer's is characterized by amyloid. First thing, you need amyloid, and then you get the tau, then the tau spreads through neuronal circuits. But at the same time, you're seeing a decline in energy metabolism in the brain, so glucose is not being metabolized properly and the brain basically is in an energy-depleted state. And so, what we are doing here is we're basically taking that different manifestation of Alzheimer's and fixing it with... At least we did that in the mice.

Nicholas Weiler (38:18):

And it improved their memory, it improved their cognitive function?

Katrin Andreasson (38:21):

Yes, it improved everything, yeah. And the interesting thing is at the same time that we were rescuing these neurons, they're working better, cognition is back, at the same time, we also found that we reduced amyloid. Why? We don't know, and that's what we're working on right now. And also, reduced this pathologic form of tau. Why? We don't know. So that's the next set, that's what we're working on. Well, actually, first, we're trying to get some NIH funding for this.

Nicholas Weiler (38:50):

Right. If any NIH program directors out there are listening to the show.

Katrin Andreasson (38:55):

Yes, hopefully.

Nicholas Weiler (38:57):

Well, yeah. So I know we've got to close, I just want to close on this last thought, that it feels like we've taken these really important steps back from focusing on the end product of what we see in late-stage Alzheimer's brains full of amyloid plaques and these tau tangles, and taking a step back to look at aging, to look at inflammation and to look at energy metabolism, these very fundamental things that are setting the groundwork for why does this disease happen with aging? Why does it get so bad? Why are all of these other things going on? Maybe we could just close with what is your hope for where we are going in the next five to 10 years of what is actually going to be a way of helping patients with this disorder, to take this back to the therapies?

Katrin Andreasson (39:44):

Yeah. Well, I think everybody is hoping for better and better biomarkers. What we need are biomarkers that can tell us 10 years ahead of when we're going to start developing cognitive decline, whether we have something, some problem, like do we have too much amyloid? We do have ways to look at this, but obviously it would be too expensive. So we need more and more sensitive biomarkers that are predictive of future disease, and that is a very active area, there's been huge progress, it's really very exciting.

(40:19):

In terms of treatments, I think we need to consider alternative approaches, and that's already being done, people are thinking about targeting inflammation. Unfortunately, the one that people had some hope with, which was targeting this very good inflammation receptor called TREM2, the clinical trials didn't show efficacy, that's very unfortunate. And I think there's a lot we can learn from those trials and we have to keep plugging away at that. But then, the final thing which I would argue is that maybe we should think about targeting brain metabolism by repurposing these cancer drugs, these IDO1 inhibitors that have already been extensively tried in cancer. So I am hopeful, as long as we can keep science funded in the United States and it's not a political issue.

Nicholas Weiler (41:17):

Right. Hopefully, Alzheimer's is not a political issue. Hopefully, we can all agree that it would be nice to treat Alzheimer's.

Katrin Andreasson (41:22):

Well, I would hope, because politicians get Alzheimer's, so maybe they will see the light.

Nicholas Weiler (41:29):

Well, thank you so much, Katrin, for coming on From Our Neurons to Yours, this has been fantastic, and I hope we can have you back as more of these exciting discoveries come out.

Katrin Andreasson (41:38):

Yeah. Thank you, Nick, thanks. It's been a pleasure. Thank you so much.

Nicholas Weiler (41:43):

Thanks again so much to our guest, Katrin Andreasson. She's the Edward F. and Irene Thiele Pimley Professor of Neurology and Neurological Sciences at Stanford Medicine. To read more about her work, check out the links in the show notes. If you're enjoying the show, please subscribe and share with your friends. It helps us grow as a show and bring more listeners to the frontiers of brain science. We'd also love to hear from you. Send us an email at neuronspodcast@stanford.edu and let us know what's working for you about the show, your favorite episodes, or questions you'd like to have us answer. Quick programming note, we're going to take a few weeks off, but we will be back in 2026 with new episodes from the frontiers of brain science. From Our Neurons to Yours is produced by Michael Osborne at 14th Street Studios, with sound design by Mark Bell. I'm Nicholas Weiler. Until next time.